Premium
mTOR/p70S6k signalling alteration by Aβ exposure as well as in APP‐PS1 transgenic models and in patients with Alzheimer's disease
Author(s) -
LafayChebassier Claire,
Paccalin Marc,
Page Guylène,
BarcPain Stéphanie,
PeraultPochat Marie Christine,
Gil Roger,
Pradier Laurent,
Hugon Jacques
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03187.x
Subject(s) - pi3k/akt/mtor pathway , genetically modified mouse , phosphorylation , senile plaques , transgene , hyperphosphorylation , microbiology and biotechnology , tau protein , autophagy , kinase , biology , astrogliosis , amyloid precursor protein , alzheimer's disease , cancer research , apoptosis , neuroscience , endocrinology , medicine , signal transduction , disease , biochemistry , central nervous system , gene
In Alzheimer's disease, neuropathological hallmarks include the accumulation of β‐amyloid peptides (Aβ) in senile plaques, phosphorylated tau in neurofibrillary tangles and neuronal death. Aβ is the major aetiological agent according to the amyloid cascade hypothesis. Translational control includes phosphorylation of the kinases mammalian target of rapamycin (mTOR) and p70S6k which modulate cell growth, proliferation and autophagy. It is mainly part of an anti‐apoptotic cellular signalling. In this study, we analysed modifications of mTOR/p70S6k signalling in cellular and transgenic models of Alzheimer's disease, as well as in lymphocytes of patients and control individuals. Aβ 1–42 produced a rapid and persistent down‐regulation of mTOR/p70S6k phosphorylation in murine neuroblastoma cells associated with caspase 3 activation. Using western blottings, we found that phosphorylated forms of mTOR and p70S6k are decreased in the cortex but not in the cerebellum (devoid of plaques) of double APP/PS1 transgenic mice compared with control mice. These results were confirmed by immunohistochemical methods. Finally, the expression of phosphorylated p70S6k was significantly reduced in lymphocytes of Alzheimer's patients, and levels of phosphorylated p70S6k were statistically correlated with Mini Mental Status Examination (MMSE) scores. Taken together, these findings demonstrate that the mainly anti‐apoptotic mTOR/p70S6k signalling is altered in cellular and transgenic models of Alzheimer's disease and in peripheral cells of patients, and could contribute to the pathogenesis of the disease.